This project investigates the neurobiological effects of the tricyclic antidepressant iprindole and the antimalarial agent chloroquine in rat brain. These amphiphilic cations, when administered daily for 5-6 weeks, elicit the widespread formation of intracellular lysosomal myeloid bodies in the nervous system and elsewhere. Results obtained to date indicate that iprindole and chloroquine produce a rapid (1 hour) activation of the lysosomal system in brain, as shown by a significant decrease in lysosomal enzyme latency in 0.3 M sucrose, and an increase in lysosomal membrane fragility on exposure to hypoosmotic and chemical challenge in vitro. The reduced enzyme latency and membrane fragility of lysosomes reflects the properties of an expanded population of lysosomes of low equilibrium density identified as autophagic vacuoles and originating partly from the major high density lysosomal fraction. Pretreatment with aspirin (75 mg/kg) or dexamethasone (4 mg/kg) attenuates the drug-induced destabilization of lysosomes. We shall investigate the ultrastructural, biochemical and metabolic effects of these agents in rat brain in relation to their intracellular concentration and subcellular distribution. Early ultrastructural changes affecting neurons and glia in cerebral and cerebellar cortex will be looked for in order to identify possible target organelles of drug action, and to assess the tempo of intracellular autophagy and myeloid body formation. The effect of drugs on the turnover rates of protein in specific subcellular fractions, e.g., mitochondria, microsomes, lysosomes, will be investigated. Particular attention will be directed to a biochemical characterization of the lipid and lipoprotein composition of drug-induced myeloid bodies and the rates of synthesis and degradation of key lipid and protein components.